Hemoglobin as a biomarker for breast cancer ISSN 2753-8176 (online) (DOI: 10.13140/RG.2.2.25461.65764)

Ana Pedro¹

1. Gwyntwr1386 Pharmacy, Regus Chester Business Park, Heronsway, Chester CH4 9QR, United Kingdom

anapedrolaboratories@gmail.com

Abstract

An enourmous amount of data and additional new data supports a role for hemoglobin in breast cancer.

Literature Review and evidence

Mammography screening is meant to reduce breast cancer (BC) mortality through early diagnosis and treatment of disease that would otherwise threaten life. However, in some cases a screening mammogram detects a cancer that would have neither caused death nor presented clinically during the woman’s lifetime(1). It is clear that to reduce the burden of over diagnosis on both the emotional and physical health of the patient and the economic health of the NHS, more sensitive tests for the diagnosis of breast cancer are needed.

Preliminary data of our lab have showed that we have identified a biomarker for early stage ER+ breast cancer, HCG1745306 isoform CRA-a (2). A large body of evidence supports a role for haemoglobin not only in breast cancer diagnosis but also in cancer diagnosis in general. Haemoglobin subunit alpha has also been previously found to be upregulated in the urine of patients with early invasive BC (3). Moreover, previous work indicated the possibility of a direct relationship between the hemoglobin level and not only the early stages of cancer, but also the chemically induced precancerous condition (4).

Total haemoglobin (THC) has been shown to be present in higher concentrations in breast tumours in comparison to healthy tissues while oxyhemoglobin has been showed to be reduced thus reflecting early metabolic changes in cancer towards hypoxia (5,6). Haemoglobin has also been shown to predict axillary staging with a multivariate analysis study showing an independent relationship between the probability of axillary metastasis and elevated total haemoglobin concentration level (THC) (7) . THC is significantly correlated with prognostic factors such as tumor size, histologic grade, ER, PR, and c-erbB-2 (8). In particular, hemoglobin beta expression (HBB) increases breast cancer cells aggressiveness and associates with poor prognosis (9). In addition, in triple-negative BC, low hemoglobin is significantly associated with decreased DFS and OS (10). Low pretreatment haemoglobin levels may also negatively influence the tumour response to primary chemotherapy in BC (11). Anaemia during adjuvant chemotherapy is also associated with poor survival in patients with primary BC (12,13). Blood hemoglobin concentration also seems to affect the prognosis of patients with early BC when a treatment schedule that includes radiotherapy is applied (14). Reduced radiosensitivity due to diminished tumor oxygenation may be the underlying cause (14).

Curiously, in patients with a diagnosis of primary lung, colorectal, breast or liver cancer, higher post-diagnosis haemoglobin change regardless of the baseline haemoglobin levels and the direction of changes associates with a significantly shorter survival(15).

Additional published data from our lab shows that HBA1, which was found to be present in urine samples of patients with early BC (3), also presents very high mascot scores in plasma samples of patients with early BC (marked in red). The mascot scores, however, drop in the plasma of patients with locally advanced BC and of patients with certain metastatic patterns (marked in blue). Also, HBA1 is not significantly present in the primary BC tumor tissues, although bone metastases, show a high score for this protein (table 1). Hemoglobin subunit beta (HBB), which was found to increase breast cancer cells aggressiveness and associates with poor prognosis (9), also presents very high mascot scores in plasma samples of patients with early BC. The mascot scores, however, drop in the plasma of patients with locally advanced BC, but are significant in the primary BC tissues what allows us to think might be secreted by the tumor (16). Bone metastases, also show a high score for this protein (table 1).

Proteins Samples	HBA1 (P69905) Chromosome 16, 172,876 - 173,710	G3V1N2 (HCG1745306, isoform CRA_a) Chromosome 16, 222,846 – 223,709	HBB (P68871) Chromosome 11, 5,229,395 - 5,225,464
Male 1 (plasma control)	970.17	-----	1369.46
Male 2 (plasma control)	476.12	------	1092.87
Female 1 (plasma control)	469.46	-------	586.95
Female 2 (plasma control)	403.45	--------	711.13
CF37 (plasma, breast cancer, LN-)	3633.78	3208.75461	4037.79
CF5 (plasma, breast cancer, LN+)	4556.25	3966.542	3176.82
CF110 (breast cancer, Locally advanced, plasma)	276.72	-------	465.85
CF1 (LN, liver metastases, plasma)	371.15	-------	653.16
CF25 (LN, liver, cartilage, skin, plasma)	494.60	-------	679.29
CF33 (LN, liver, bone, skin, lung, brain, plasma)	474.03	-------	785.82
CF27 (LN, lung, bone, plasma)	397.54	-------	648.41
SKBC (Multiple metastasis, plasma)	246.49	-------	669.33
Parental breast cancer (primary tumor)	81.68 (NS)	--------	147.50 (S) Secreted by the tumor?
BC1 (bone metastases)	2024.74	---------	2419.45
BC2 (bone metastases)	1371.04	--------	1936.45

Table 1: Mascot scores for HBA1, CRA-a, and HBB in different BC samples. LF, lymphatic fluid, NS- non-significant, S-significant.

Methods

All samples files and methods details can be found at Tucker R, Pedro A. Blood-derived non-extracellular vesicle proteins as potential biomarkers for the diagnosis of early ER+ breast cancer and detection of lymph node involvement. F1000research (2018) DOI:10.12688/f1000research.14129.3.

Samples CF37, CF5, CF1, CF25, CF33, CF27, and CF110 and C7 (female control plasma sample) were collected at Champalimaud Clinical Centre, Portugal, as part of a study on the role of tumor-derived microvesicles and bone marrow progenitor cells as diagnostic and prognostic biomarkers in advanced BC and inflammatory BC Patients (RECI/BIM-ONC/0201/2012, FCT, Portugal).

References

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